The invention relates to triazole compounds and to the use of these compounds. These compounds possess valuable therapeutic properties and can be used for treating diseases which respond to the influence of dopamine D3 receptor ligands.
Compounds of the type which is under discussion here and which possess physiological activity are already known. Thus, WO 94/25013; 96/02520; 97/43262; 97/47602; 98/06699; 98/49145; 98/50363; 98/50364 and 98/51671 describe compounds which act on the dopamine receptors. DE 44 25 144 A, WO 96/30333, WO 97/25324, WO 97/40015, WO 97/47602, WO 97/17326, EP 887 350, EP 779 284 A and Bioorg. and Med. Chem. Letters 9 (1999) 2059-2064 disclose further compounds which possess activity as dopamine D3 receptor ligands. U.S. Pat. Nos. 4,338,453; 4,408,049 and 4,577,020 disclose triazole compounds which possess antiallergic or antipsychotic activity. WO 93/08799 and WO 94/25013 describe compounds of the type which is under discussion here and which constitute endothelin receptor antagonists. Additional triazole compounds, which inhibit blood platelet aggregation and which have a hypotensive effect are described in Pharmazie 46 (1991), 109-112. Further triazole compounds which possess physiological activity are disclosed in EP 691 342, EP 556 119, WO 97/10210, WO 98/24791, WO 96/31512 and WO 92/20655.
Neurons obtain their information by way of G protein-coupled receptors, inter alia. There are a large number of substances which exert their effect by way of these receptors. One of them is dopamine.
A number of facts about the presence of dopamine, and its physiological function as a neuron transmitter, are known with certainty. Disturbances of the dopaminergic transmitter system result in diseases such as schizophrenia, depression and Parkinson""s disease. These, and other, diseases are treated with drugs which interact with the dopamine receptors.
By 1990, two subtypes of dopamine receptor had been clearly defined pharmacologically, namely the D1 and D2 receptors.
More recently, a third subtype has been found, namely the D3 receptor, which appears to mediate some of the effects of the antipsychotic and anti-Parkinson agents (J. C. Schwartz et al., The Dopamine D3 Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging 1998, 12, 495-514).
Since D3 receptors are chiefly expressed in the limbic system, it is assumed that while a selective D3 ligand would probably have the properties of known antipsychotic agents, it would not have their dopamine D3 receptor-mediated neurological side-effects (P. Sokoloff et al., Localization and Function of the D3 Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D3) as a Target for Neuroleptics, Nature, 347, 146 (1990)).
Surprisingly, it has now been found that certain triazole compounds exhibit a high affinity for the dopamine D3 receptor and a low affinity for the D2 receptor. These compounds are consequently selective D3 ligands.
The present invention relates, therefore, to the compounds of the formula I: 
where
R1 is H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C3-C6-cycloalkyl or phenyl;
R2 is H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C1-C6-alkoxy, C1-C6-alkylthio, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, halogen, CN, COOR3, CONR3R4, NR3R4, SO2R3, SO2NR3R4, or an aromatic radical which is selected from phenyl, naphthyl and a 5- or 6-membered-heterocyclic radical having 1, 2, 3 or 4 heteroatoms which are selected, independently of each other, from O, N and S, with it being possible for the aromatic radical to have one or two substituents which are selected, independently of each other, from C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, halogen, CN, COR3, NR3R4, NO2, SO2R3, SO2NR3R4 and phenyl which may be substituted by one or two radicals which are selected, independently of each other, from C1-C6-alkyl, C1-C6-alkoxy, NR3R4, CN, CF3, CHF2 or halogen;
R3 and R4 are, independently of each other, H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, or phenyl;
A is C4-C10-alkylene or C3-C10-alkylene which comprises at least one group Z which is selected from O, S, CONR3, COO, CO, C3-C6-cycloalkyl and a double or triple bond;
B is a radical of the following formula: 
X is CH2 or CH2CH2;
R5 is H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C3-C6-cycloalkyl, C2-C6-alkenyl, which may be substituted by halogen (1 or 2 halogen atoms), or C2-C6-alkynyl;
R6, R7 and R8 are, independently of each other, selected from H, C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, C1-C6-alkylthio, halogen or phenyl, OH, C1-C6-alkoxy, SH, C1-C6-alkylthio, C2-C6-alkenyl, C2-C6-alkynyl, halogen, CN, NO2, SO2R3, SO2NR3R4, CONR3R4, NHSO2R3 and NR3R4;
and the salts thereof with physiologically tolerated acids.
The compounds according to the invention are selective dopamine D3 receptor ligands which act in the limbic system in a regioselective manner and which, as a result of their low affinity for the D2 receptor, have fewer side-effects than do the classic neuroleptic agents, which are D2 receptor antagonists. The compounds can therefore be used for treating diseases which respond to dopamine D3 ligands, i.e. they are effective for treating those diseases in which affecting (modulating) the dopamine D3 receptors leads to an improvement in the clinical picture or to the disease being cured. Examples of such diseases are diseases of the cardiovascular system and the kidneys, diseases of the central nervous system, in particular schizophrenia, affective disorders, neurotic stress and somatoform disorders, psychoses, parkinsonism, attention deficit disorders, hyperactivity in children, epilepsy, amnesic and cognitive disorders such as learning and memory impairment (impaired cognitive function), anxiety states, dementia, delirium, personality disorders, sleep disturbances (for example restless legs syndrome), disorders of the sex life (male impotence), eating disorders and addictive disorders. Moreover, they are useful in the treatment of stroke.
Addictive disorders include the pysychological disorders and behavioral disturbances caused by the abuse of psychotropic substances such as pharmaceuticals or drugs, and other addictive disorders such as, for example, compulsive gambling (impluse control disorders not elsewhere classified). Addictive substances are, for exampel: opioids (for example morphine, heroin, codeine); cocaine; nicotine; alcohol; substances which interact with the GABA chloride canal complex, sedatives, hypnotics or tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3,4-methylendioxy-N-methylamphetamine (ecstasy); amphetamine and amphetamine-like substances such as methylphenidate or other stimulants including caffeine. Addictive substances of particular concern are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol.
The compounds according to the invention are preferably used for treating affective disorders; neurotic, stress and somatoform disorders and psychoses, e.g. schizophrenia.
Within the context of the present invention, the following expressions have the meanings given in conjunction with them:
Alkyl (also in radicals such as alkoxy, alkylthio, alkylamino etc.) is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms and, in particular from 1 to 4 carbon atoms. The alkyl group can have one or more substituents which are selected, independently of each other, from OH, OC1-C6-alkyl, halogen or phenyl. In the case of a halogen substituent, the alkyl group can, in particular, encompass, 1, 2, 3 or 4 halogen atoms which can be located on one or more C atoms, preferably in the xcex1 or xcfx89 position. CF3, CHF2, CF2Cl or CH2F are particularly preferred.
Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, etc.
Cycloalkyl is, in particular, C3-C6-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Alkylene radicals are straight-chain or branched. If A does not have a group Z, A then comprises from 4 to 10 carbon atoms, preferably from 4 to 8 carbon atoms. The chain between the triazole nucleus and group B then has at least four carbon atoms. If A has at least one of said Z groups, A then comprises from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms.
If the alkylene groups comprise at least one of the Z groups, this or these groups can then be arranged in the alkylene chain at an arbitrary site or in position 1 or 2 of the A group (seen from the triazole radical). The radicals CONR2 and COO are preferably arranged such that the carbonyl group is in each case facing the triazole ring. Particular preference is given to the compounds of the formula I in which A is xe2x80x94Zxe2x80x94C3-C6-alkylene, in particular xe2x80x94Zxe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94Zxe2x80x94CH2CH2CH2CH2xe2x80x94, xe2x80x94Zxe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94, xe2x80x94Zxe2x80x94CH2C(CH3)xe2x95x90CHCH2xe2x80x94, 
xe2x80x94Zxe2x80x94CH2CH(CH3)CH2xe2x80x94 or a linear xe2x80x94Zxe2x80x94C7-C10-alkylene radical, with Z being bonded to the triazole ring. Z is preferably CH2, O and, in particular, S. Preference is additionally given to A being xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2CH2CHxe2x95x90CHCH2xe2x80x94, 
xe2x80x94CH2CH2C(CH3)xe2x95x90CHCH2xe2x80x94 or xe2x80x94CH2CH2CH(CH3)CH2xe2x80x94.
Halogen is F, Cl, Br or I, preferably F or Cl.
R1 is preferably H, C1-C6-alkyl or C3-C6-cycloalkyl.
If R2 is an aromatic radical, this radical is then preferably one of the following radicals: 
where
R9 to R11 are H or the abovementioned substituents of the aromatic radical,
R12 is H, C1-C6-alkyl or phenyl, and
T is N or CH.
If the phenyl radical is substituted, the substituents are preferably in the m position or the p position.
The aromatic radical is particularly preferably a group of the formula: 
where R9, R10 and R12 have the abovementioned meanings. The indicated phenyl, pyridyl, thiazolyl and pyrrole radicals are particularly preferred.
The radicals R9 to R11 are preferably H, C1-C6-alkyl, OR3, CN, phenyl, which may be substituted by C1-C6-alkyl, C1-C6-alkoxy or halogen, CF3 and halogen, and are, in particular, H, C1-C6-alkyl, OR3 and halogen. In this context, R3 has the abovementioned meanings.
Particularly preferably, R2 is H, C1-C6-alkyl, NR3R4 (R3 and R4 are, independently of each other, H or C1-C6-alkyl), phenyl or a 5-membered aromatic heterocyclic radical which has 1 or 2 heteroatoms which are independently selected from N, S and O. The heterocyclic radical is preferably a pyrrole radical or a pyridine radical.
In the radical B, X is preferably CH2CH2.
Preferably, at least one of the radicals R6, R7 and R8 is H.
The radicals R6, R7 and R8 are preferably, and independently of each other, selected from H, C1-C6-alkyl, halogen-substituted C1-C6-alkyl, OH, C1-C6-alkoxy, C1-C6-alkylthio-C1-C6-alkyl, halogen, NO2, CN, SO2R3, SO2NR3R4 and CONR3R4. Particularly preferably, the fused phenyl group has one or two substituents, i.e. one or two of the radicals R6, R7 and R8 is/are C1-C6-alkyl, halogen, CN, SO2NR3R4, NO2 or CF3.
Particular preference is given to the compounds of formula I where
R1 is H, C1-C6-alkyl or phenyl,
R2 is H, C1-C6-alkyl, phenyl, thienyl, furanyl, pyridyl, pyrrolyl, thiazolyl or pyrazinyl,
A is xe2x80x94SC3-C10-alkylene which can comprise a double bond or C3-C6-cycloalkyl, and
R6, R7 and R8 are selected from H, C1-C6-alkyl, C1-C6-alkoxy, halogen, SO2NR3R4, CN, NO2 or CF3.
The invention also encompasses the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other acids which can be used are described in Fortschritte der Arzneimittelforschung [Advances in pharmaceutical research], Volume 10, pages 224 ff., Birkhxc3xa4user Verlag, Basle and Stuttgart, 1966.
The compounds of the formula I can exhibit one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The respective tautomeric forms are also included in the invention.
The process for preparing the compounds of the formula I consist in
a) reacting a compound of the formula (II) 
where Y1 is a customary leaving group, such as Hal, alkylsulfonyloxy, arylsulfonyloxy, etc., with a compound of the formula (III)
HBxe2x80x83xe2x80x83(III);
or
b) reacting a compound of the formula (IV) 
where Z1 is O or S, and A1 is C1-C10-alkylene or a bond, with a compound of the formula (V)
Y1xe2x80x94A2xe2x80x94Bxe2x80x83xe2x80x83(V)
where Y1 has the abovementioned meaning and A2 is C2-C10-alkylene, with A1 and A2 together having from 3 to 10 C atoms and A1 and/or A2 where appropriate comprising at least one group Z; or
c) reacting a compound of the formula (VI) 
where Y1 and A1 have the abovementioned meanings, with a compound of the formula (VII)
Hxe2x80x94Z1xe2x80x94Axe2x80x94Bxe2x80x83xe2x80x83(VII)
where Z1 has the abovementioned meanings; or
d) reversing the polarity of a compound of the formula (VIII) 
using reagents which are known from the literature, such as 1,3-propanedithiol, KCN/water, TMSCN (trimethylsilyl cyanide) or KCN/morpholine, as described, for example, in
Albright Tetrahedron, 1983, 39, 3207 or
D. Seebach Synthesis 1969, 17 und 1979, 19 or
H. Stetter Angew. Chem. Int. Ed. 1976, 15, 639 or
van Niel et al. Tetrahedron 1989, 45, 7643
Martin et al. Synthesis 1979, 633,
to give the products (VIIIa) (using 1,3-propanedithiol by way of example) 
and then chain-elongating with compounds of the formula (IX)
Y1xe2x80x94A3xe2x80x94Bxe2x80x83xe2x80x83(IX)
where Y1 has the abovementioned meaning and A3 is C3-C9-alkylene which can contain a group Z, with compounds of the formula (Ia) 
where Z2 is CO or a methylene group, and Z2 and A2 have together from 4 to 10 C atoms, being obtained after deprotecting or reducing, or
e) reacting a compound of the formula (VIII) with a compound of the formula (X)
Y2xe2x80x94Axe2x80x94Bxe2x80x83xe2x80x83(X)
where Y2 is a phosphorane or a phosphonic ester, in analogy with customary methods, as described, for example, in Houben Weyl xe2x80x9cHandbuch der Organischen Chemiexe2x80x9d [Textbook of Organic Chemistry], 4th Edition, Thieme Verlag Stuttgart, Volume V/1b p. 383 ff, or Vol. V/1c p. 575 ff, or
f) reacting a compound of the formula (XI) 
where Q is H or OH, with a compound of the formula III under reductive conditions in analogy with methods known from the literature, for example as described in J. Org. Chem. 1986, 50, 1927; or WO 92/20655, or
g) in order to prepare a compound of the formula (Ib) 
where B1 is a radical of the formula (XII) 
reacting compounds of the formula (XIII) or (XIV), 
with a compound of the formula (XV) 
under reductive conditions.
The process for preparing a compound of the formula I where A comprises the groups COO or CONR3 consists in reacting a compound of the formula (XVI) 
where Y3 is OH, OC1-C4-alkyl, Cl or, together with CO, an activated carboxyl group, and A4 is C0-C9-alkylene, with a compound of the formula (XVII)
Bxe2x80x94Axe2x80x94Z3xe2x80x83xe2x80x83(XVII)
where Z3 is OH or NHR3.
Compounds of the type (XV) can be synthesized by alkylating compounds of the formula (IV) with compounds of the formula (XVIII), 
to give compounds of the formula (XIX), 
subsequently carrying out hydrazinolysis to give compounds of the type (XX) 
and then introducing the radical R5, by, for example, effecting a reductive amination (as described, for example, in J. Org. Chem. 1986, 50, 1927) using the corresponding aldehyde or by means of alkylation in the presence of a base.
Compounds of the formula XX can also be obtained by reacting compounds of the formula II with azides, such as sodium azide, and then reducing, as described, for example, in
H. Staudinger, Helv. Chim. Acta 1919, 2, 635 or
R. Carrie, Bull. Chem. Soc. Fr. 1985, 815.
Compounds of the formula XIII and XIV are known from the literature or can be prepared using known methods, as described, for example, in
A. van Vliet et al. J. Med. Chem. 1996, 39, 4233
M. Langlois Bioorg. Med. Chem. Lett. 1993, 3, 203
U. Hacksell J. Med. Chem. 1993, 36, 4221 or in WO 93/08799 or WO 95/04713.
The compounds of the formula (IV) type are either known or can be prepared using known methods, as described, for example, in A. R. Katritzky, C. W. Rees (ed.) xe2x80x9cComprehensive Heterocyclic Chemistryxe2x80x9d, Pergamon Press, or xe2x80x9cThe Chemistry of Heterocyclic Compoundsxe2x80x9d J. Wiley and Sons Inc. NY and the literature which is cited therein, or in S. Kubota et al. Chem. Pharm. Bull. 1975, 23, 955 or Vosilevskii et al. Izv. Akad. Nauk. SSSR Ser. Khim. 1975, 23, 955.
In the above formulae, R1, R2, R5, R6, R7, R8, A, B and X have the meanings given in connection with formula I.
The compounds according to the invention, and the starting materials and the intermediates, can also be prepared in analogy with the methods which are described in the patent publications which were mentioned at the outset.
The above-described reactions are generally effected in a solvent at temperatures of between room temperature and the boiling temperature of the solvent employed. Examples of solvents which can be used are esters, such as ethyl acetate, ethers, such as diethyl ether or tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, acetonitrile, ketones, such as acetone or methyl ethyl ketone, or alcohols, such as ethanol or butanol.
If desired, the reactions can be carried out in the presence of an acid-binding agent. Suitable acid-binding agents are inorganic bases, such as sodium carbonate or potassium carbonate, or sodium hydrogencarbonate or potassium hydrogencarbonate, sodium methoxide, sodium ethoxide, sodium hydride, or organometallic compounds, such as butyl lithium or alkyl magnesium compounds, or organic bases, such as triethylamine or pyridine. The latter can also simultaneously serve as the solvent.
Processes (f) and (g) are effected under reducing conditions, e.g. using sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride, where appropriate in an acid medium or in the presence of a Lewis acid, such as zinc chloride, or by way of catalytic hydrogenation.
The crude product is isolated in a customary manner, for example by means of filtering, distilling off the solvent or extracting from the reaction mixture, etc. The resulting compounds can be purified in a customary manner, for example by recrystallization from a solvent, by chromatography or by converting into an acid addition compound.
The acid addition salts are prepared in a customary manner by mixing the free base with the corresponding acid, where appropriate in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.
For treating the abovementioned diseases, the compounds according to the invention are administered orally or parenterally (subcutaneously, intravenously, intramuscularly or intraperitoneally) in a customary manner. The administration can also be effected through the nasopharyngeal space using vapors or sprays.
The dosage depends on the age, condition and weight of the patient and on the type of administration. As a rule, the daily dose of active compound is from about 10 to 1000 mg per patient and day when administered orally and from about 1 to above 500 mg per patient and day when administered parenterally.
The invention also relates to pharmaceuticals which comprise the compounds according to the invention. In the customary pharmacological administration forms, these pharmaceuticals are present in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or sprays. In this context, the active compounds can be worked up together with the customary pharmacological auxiliary substances, such as tablet binders, fillers, preservatives, tablet disintegrants, flow-regulating agents, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents, antioxidants and/or propellent gases (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The resulting administration forms normally comprise the active compound in a quantity of from 1 to 99% by weight.